Abstract
The lymphatic system is essential for transporting interstitial fluid, soluble antigen, and immune cells from peripheral tissues to lymph nodes (LNs). Functional integrity of LNs is dependent on intact lymphatics and effective lymph drainage. Molecular mechanisms that facilitate interactions between tumor cells and lymphatic endothelial cells (LECs) during tumor progression still remain to be identified. The cellular and molecular structures of LNs are optimized to trigger a rapid and efficient immune response, and to participate in the process of tumor metastasis by stimulating lymphangiogenesis and establishing a premetastatic niche in LNs. Several molecules, e.g., S1P, CCR7-CCL19/CCL21, CXCL12/CXCR4, IL-7, IFN-γ, TGF-β, and integrin α4β1 play an important role in controlling the activity of LN stromal cells including LECs, fibroblastic reticular cells (FRCs) and follicular dendritic cells (DCs). The functional stromal cells are critical for reconstruction and remodeling of the LN that creates a unique microenvironment of tumor cells and LECs for cancer metastasis. LN metastasis is a major determinant for the prognosis of most human cancers and clinical management. Ongoing work to elucidate the function and molecular regulation of LN lymphatic sinuses will provide insight into cancer development mechanisms and improve therapeutic approaches for human malignancy.
Highlights
The lymphatic system plays an active role in modulating inflammation, autoimmune disease, and anti-tumor immune response
The sensitivity of lymph node lymphatic endothelial cells (LN-LECs), the cells derived from intranodal lymphatic sinuses to the dynamic tumor microenvironment remains poorly understood, they should no longer be considered a passive bystander in tumor metastasis but rather an active player in many intercellular and intracellular processes [12,13]
This review aims to assess the remodeling and reconstruction, as well as immune involvement of lymph nodes (LNs) lymphatic sinuses during tumor metastasis, with emphasizing the interaction between tumor cells and LN-LECs including lymphangiogenesis
Summary
The lymphatic system plays an active role in modulating inflammation, autoimmune disease, and anti-tumor immune response. E.g., cancer and inflammation, LNs undergo dramatic remodeling including changes in immune cell trafficking and cellularity, and lymph flow [5]. Lymphatic endothelial cells (LECs) are emerging as important players in modulating adaptive immune responses, presenting tumor antigen and inducing immune tolerance. The sensitivity of lymph node lymphatic endothelial cells (LN-LECs), the cells derived from intranodal lymphatic sinuses to the dynamic tumor microenvironment remains poorly understood, they should no longer be considered a passive bystander in tumor metastasis but rather an active player in many intercellular and intracellular processes [12,13]. This review aims to assess the remodeling and reconstruction, as well as immune involvement of LN lymphatic sinuses during tumor metastasis, with emphasizing the interaction between tumor cells and LN-LECs including lymphangiogenesis. LN-LECs represent attractive therapeutic targets to enhance tumor immunotherapy and to control tumor metastasis
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